Extending Residence Time and Stability of Peptides by Protected Graft Copolymer (PGC) Excipient: GLP-1 Example
- 217 Downloads
To determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes.
To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups. We performed evaluation of the binding of excipient to GLP-1, the DPP IV sensitivity of GLP-1 formulated with PGC as the excipient, the in vitro bio-activity of excipient-formulated GLP-1, the in vivo pharmacokinetics of excipient-formulated GLP-1, and the efficacy of the excipient-formulated GLP-1 in diabetic rats.
We showed reproducible synthesis of PGC excipient, high affinity binding of PGC to GLP-1, slowed protease degradation of excipient-formulated GLP-1, and that excipient-formulated GLP-1 induced calcium influx in INS cells. Excipient-formulated GLP-1 stays in the blood for at least 4 days. When excipient-formulated GLP-1 was given subcutaneously once a week to diabetic ZDF rats, a significant reduction of HbA1c compared to control was observed. The reduction is similar to diabetic ZDF rats given exendin twice a day.
PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides.
KEY WORDSdiabetes glucagon like peptide peptide excipient protected graft copolymer
- DPP IV
dipeptidyl peptidase IV
poly(ethylene glycol) conjugation
protected graft copolymer
ACKNOWLEDGMENTS & DISCLOSURES
This work was supported by the SBIR Grant #DK069727 from National Institute of Diabetes and Digestive and Kidney diseases of the National Institute of Health. The authors thank Ms. Cynthia Jones, Ms. Akiko Nishimoto-Ashfield, and Ms. Marisa Robinson for assistance with the manuscript.
- 8.Amylin Pharmaceuticals. http://www.rxlist.com/cgi/generic4/byetta_ad.htm. 2008.
- 12.BYETTA. prescribing information [article online, revised june 2008], URL: http://pi.lilly.com/us/byetta-pi.pdf.
- 24.Young AA, Gedulin BR, Bhavsar S, Bodkin N, Jodka C, Hansen B, et al. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes. 1999;48(5):1026–34.PubMedCrossRefGoogle Scholar